Parasite-derived neurotrophic factor/trans-sialidase of Trypanosoma cruzi links neurotrophic signaling to cardiac innate immune response.

The Chagas' disease parasite Trypanosoma cruzi elicits a potent inflammatory response in acutely infected hearts that keeps parasitism in check and triggers cardiac abnormalities. A most-studied mechanism underlying innate immunity in T. cruzi infection is Toll-like receptor (TLR) activation by lipids and other parasite molecules.

Trypanosoma cruzi coaxes cardiac fibroblasts into preventing cardiomyocyte death by activating nerve growth factor receptor TrkA.

Rationale: Cardiomyocytes express neurotrophin receptor TrkA that promotes survival following nerve growth factor (NGF) ligation. Whether TrkA also resides in cardiac fibroblasts (CFs) and underlies cardioprotection is unknown.

Objective: To test whether CFs express TrkA that conveys paracrine signals to neighbor cardiomyocytes using, as probe, the Chagas disease parasite Trypanosoma cruzi, which expresses a TrkA-binding neurotrophin mimetic, named PDNF.

Trypanosoma cruzi highjacks TrkC to enter cardiomyocytes and cardiac fibroblasts while exploiting TrkA for cardioprotection against oxidative stress.

Chronic Chagas cardiomyopathy (CCC), caused by the obligate intracellular protozoan parasite Trypanosoma cruzi, is a major cause of morbidity and mortality in Latin America. CCC begins when T. cruzi enters cardiac cells for intracellular multiplication and differentiation, a process that starts with recognition of host-cell entry receptors.

Neurodegeneration and neuroregeneration in Chagas disease.

Autonomic dysfunction plays a significant role in the development of chronic Chagas disease (CD). Destruction of cardiac parasympathetic ganglia can underlie arrhythmia and heart failure, while lesions of enteric neurons in the intestinal plexuses are a direct cause of aperistalsis and megasyndromes. Neuropathology is generated by acute infection when the parasite, though not directly damaging to neuronal cells, elicits immune reactions that can become cytotoxic, inducing oxidative stress and neurodegeneration.

Neurotrophin receptor TrkC is an entry receptor for Trypanosoma cruzi in neural, glial, and epithelial cells.

Trypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated by T. cruzi surface trans-sialidase, also known as parasite-derived neurotrophic factor (PDNF).

Trypanosoma cruzi-Derived Neurotrophic Factor: Role in Neural Repair and Neuroprotection.

Some patients infected with the parasite Try-panosoma cruzi develop chronic Chagas' disease, while others remain asymptomatic for life. Although pathological mechanisms that govern disease progression remain unclear, the balance between degeneration and regeneration in the peripheral nervous system seems to contribute to the different clinical outcomes. This review focuses on certain new aspects of host-parasite interactions related to regeneration in the host nervous system induced by the trans-sialidase of T.

Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy.

The parasite Trypanosoma cruzi, which causes Chagas' disease, differentiates in the cytosol of its host cell and then replicates and spreads infection, processes that require the long-term survival of the infected cells. Here, we show that in the cytosol, parasite-derived neurotrophic factor (PDNF), a trans-sialidase that is located on the surface of T. cruzi, is both a substrate and an activator of the serine-threonine kinase Akt, an antiapoptotic molecule.

Trypanosoma cruzi promotes neuronal and glial cell survival through the neurotrophic receptor TrkC.

Trypanosoma cruzi, the agent of Chagas' disease, promotes neuron survival through receptor tyrosine kinase TrkA and glycosylphosphatidylinositol-anchored glial cell-derived family ligand receptors (GFRalpha). However, these receptors are expressed by only a subset of neurons and at low levels or not at all in glial cells. Thus, T.

Preferential brain homing following intranasal administration of Trypanosoma cruzi.

The Chagas' disease parasite Trypanosoma cruzi commonly infects humans through skin abrasions or mucosa from reduviid bug excreta. Yet most studies on animal models start with subcutaneous or intraperitoneal injections, a distant approximation of the skin abrasion route. We show here that atraumatic placement of T.

Human autoantibodies specific for neurotrophin receptors TrkA, TrkB, and TrkC protect against lethal Trypanosoma cruzi infection in mice.

Patients with Chagas' disease remain asymptomatic for many years, presumably by keeping the etiological agent Trypanosoma cruzi in check through protective immunity against. Recently, we found that T. cruzi uses TrkA, a receptor tyrosine kinase responsive to neurotrophin nerve growth factor in vertebrate nervous systems, to invade cells.

A novel immunoprecipitation strategy identifies a unique functional mimic of the glial cell line-derived neurotrophic factor family ligands in the pathogen Trypanosoma cruzi.

The journey of the Chagas' disease parasite Trypanosoma cruzi in the human body usually starts in the skin after an insect bite, when trypomastigotes get through the extracellular matrix to bind specific surface receptors in the epidermis and dermis to enter cells, where they differentiate and replicate. As the infection spreads to the heart, nervous system, and other parts of the body via the circulatory system, the parasite must also cope with additional receptors in the immune system and vascular endothelium. The molecular underpinnings that govern host cell receptor recognition by T.

Chagas' disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells.

A parasite-derived neurotrophic factor (PDNF) produced by the Chagas' disease parasite Trypanosoma cruzi binds nerve growth factor (NGF) receptor TrkA, increasing receptor autophosphorylation, and activating phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/Erk) pathways, and transcription factor CREB. The end-result is enhanced survival and neuritogenesis of various types of neurons. PDNF also enhances the expression and activity of tyrosine hydroxylase, a rate limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters.

The Chagas' disease parasite Trypanosoma cruzi exploits nerve growth factor receptor TrkA to infect mammalian hosts.

Trypanosoma cruzi, the agent of Chagas' disease, is an obligate intracellular parasite that invades various organs including several cell types in the nervous system that express the Trk receptor tyrosine kinase. Activation of Trk is a major cell-survival and repair mechanism, and parasites could use Trks to invade cells as a strategy to protect their habitat and prolong parasitism of vertebrate hosts. We show that T.

Cryptosporidium p30, a galactose/N-acetylgalactosamine-specific lectin, mediates infection in vitro.

Cryptosporidium sp. cause human and animal diarrheal disease worldwide. The molecular mechanisms underlying Cryptosporidium attachment to, and invasion of, host cells are poorly understood.

Enhancement of tyrosine hydroxylase expression and activity by Trypanosoma cruzi parasite-derived neurotrophic factor.

A parasite-derived protein, PDNF, produced by the Chagas' disease agent Trypanosoma cruzi, functionally mimics mammalian neurotrophic factors by delaying apoptotic death and promoting survival and differentiation of neurons, including dopaminergic cells, through the activation of nerve growth factor receptor TrkA. Because it is well established that neurotrophic factors regulate enzymes involved in the biosynthesis of neurotransmitters, we examined whether PDNF could also directly activate tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. We found that primary cultures of rat ventral mesencephalon responded to PDNF by increasing the number of TH-positive neurons and, most importantly, preserved expression of TH in neurons treated with Parkinson disease-inducing neurotoxin 1-methyl-4-phenyl pyridinium (MPP(+)).

A synthetic peptide modeled on PDNF, Chagas' disease parasite neurotrophic factor, promotes survival and differentiation of neuronal cells through TrkA receptor.

The human parasite Trypanosoma cruzi, the agent of Chagas' disease, expresses a membrane-bound neuraminidase/trans-sialidase, also known as parasite-derived neurotrophic factor, PDNF, because it binds and activates nerve growth factor (NGF) receptor TrkA in neuronal cells. Here, we identify a 21 amino acid region (425GNASQNVWEDAYRCVNASATAN445) of PDNF that reproduces its neurotrophic activities. Synthetic peptide Y21, modeled on this sequence, induces survival and neurite outgrowth in primary dorsal root ganglion neurons.

Chagas' disease parasite promotes neuron survival and differentiation through TrkA nerve growth factor receptor.

TrkA is a receptor tyrosine kinase activated primarily by nerve growth factor (NGF) to regulate differentiation, survival, and other important functions of neurons. Given the critical role TrkA plays in neural maintenance, it may be that microbial invaders of the nervous system utilize this receptor to reduce tissue damage for maximizing host-parasite equilibrium. Candidate pathogens could be those, like Trypanosoma cruzi, which may produce relatively little brain or nerve damage in long-lasting infections.